Is CBS p.Ala183Val (c.548C>T) pathogenic?

CBS p.Ala183Val (c.548C>T) is classified Uncertain significance in CBS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-09-01). AlphaMissense: ambiguous (0.4322); Absent from gnomAD v4.1; Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is CBS p.Ala183Val (c.548C>T) in the general population?

CBS p.Ala183Val (c.548C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBS p.Ala183Val (c.548C>T)?

AlphaMissense predicts ambiguous (score 0.4322) — an in-silico prediction, not a clinical call.

CBS p.Ala183Val

Q: What condition is associated with CBS p.Ala183Val (c.548C>T)?

CBS p.Ala183Val (c.548C>T) is associated with familial thoracic aortic aneurysm and aortic dissection, classic homocystinuria (ClinVar).

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.548C>T · rs374464810 · VCV263808

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4322 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.4322	ambiguous
REVEL	0.87	moderately pathogenic-leaning
SaProt	LLR -10.04	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 1.2, phastCons 1
Regional constraint	o/e 0.24	constrained · MANE · 1,046 bp · p 7.5e-10 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CBS
Protein: p.Ala183Val
Coding: c.548C>T
MANE Select: NM_000071
dbSNP: rs374464810
Type: single nucleotide variant
Location: chr21:43065505 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 183: an α-helix

Full CBS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: classic homocystinuria

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

CBS p.Ala183Gly Uncertain significance ★ ⚠ same residue
CBS c.1145+1G>A Pathogenic/Likely pathogenic ★★ same condition
CBS c.1223+1G>T Pathogenic ★★ same condition
CBS c.1224-2A>C Pathogenic ★★ same condition
CBS c.1358+1G>A Pathogenic ★★ same condition
CBS c.1359-1G>C Pathogenic/Likely pathogenic ★★ same condition
CBS c.1468-1G>A Likely pathogenic ★★ same condition
CBS c.1552+1G>A Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cbs-p-ala183val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown